Metallocenes as anti-tumor drugs

Details Metallocenes as anti-tumor drugs Metallocenes as anti-tumor drugs

1995-02-17

1996-03-05

Nazario-Gonzalez, Porfirio

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

556 53, 556 54, 556 55, 556 56, A61K 3128, C07F 1700, C07F 728

Patent

active

054968542

DESCRIPTION:

BRIEF SUMMARY
This application is a request for U.S. examination under 35 U.S.C. .sctn.371 of International application No. PCT/US93/07875, filed Aug. 19, 1993.
The present invention relates to new titanocene compounds. More particularly the invention relates to new titanocene complexes and methods for their preparation, which possess chemotherapeutic activity being useful for the treatment of human tumors.


BACKGROUND OF THE INVENTION

There are known metallocene complexes containing titanium, vanadium, niobium and molibdenum as a metal ion, which are active against a variety of tumor cell lines such as B16 melanoma, colon 38 carcinoma, Lewis lung carcinoma, etc. It has been shown that the activity of vanadium complexes related to the formula Cp.sub.2 VCl.sub.2 where C.sub.p is cyclopentadiene, against human epidermoid (HEP-2) tumor cells in vitro and against mouse tumor cells, is similar to that of cis-platin (Murthy M. S. et el. Proc. Am. Assoc. Cancer Res. 1986, 27, 279). A study which was carried out with a corresponding molibdenum compound, supports the possibility that these complexes are binding 5'-phosphate terminated polynucleotides, thus inhibiting DNA replication, by a mechanism which different from that of cis-platinum complexes (Kon, L. Y. et al. J. Am. Chem. Soc. 1991, 113, 9027).
Titanocene dichloride, one of the first metallocene compounds which was tested, was found to be indeed a very reactive anti-tumor reagent. Due to its rapid hydrolysis to the corresponding dihydroxy derivative, it is quite reasonable to assume that this dihydroxy titanocene is the actual drug. Accordingly, many references can be found describing titanocene compounds which were tested in an attempt to possess an improved cytotoxity. Examples of such compounds include halides, pseudohalides, carboxylates, and phenolates. However, no significant improvement over titanocene dichloride in the antitumor activity has been achieved.
The metallocene diacido complexes, having the general formula (C.sub.5 H.sub.5).sub.2 MX.sub.2 are characterized by the following structural features: central metal atom and arranged in adjacent "cis-like" position. cyclopentadienyl rings.
Attempts to modify the cyclopentadienide rings lead to a decreased biological activity.
In a very recent U.S. Pat. No. 5,002,969 there are described cytostatic pharmaceutical compositions based on titanocene complexes. A group which is present in all these complexes is an amino or substituted amino bound to the titanoceno moiety. These compounds are obtained by a reaction between a titanocene dihalogenide and an amino phenol, lithium aminophenolate, or lithium amino thiophenolate. There is mentioned that the compounds have a better solubility in water than titanocene dichloride, fact which improves their application and dosing. Other titanocene complexes which were described, differ by their ionic character from the neutral titanocene compounds. Most of them correspond to the general formula [(C.sub.5 H.sub.5).sub.2 TiXL].sup.+ Y.sup.- where X and Y are anions and L is a neutral donor molecule. These ionic titanocene complexes are characterized by their improved water solubility compared with the neutral titanocene compounds.
It is an object of the present invention to provide novel titanocene derivatives. It is another object of the present invention to provide novel titanocene derivatives which possess a superior cytotoxic activity than the cis-platinum complexes.


BRIEF DESCRIPTION OF THE INVENTION

The invention relates to novel titanocene derivatives which comprise two cyclopentadiene rings linked to titanium as a central atom, which are bound covalently to two phenoxy groups which possess a substituent R which is selected from the group consisting of: COOCH.sub.3, COOC.sub.2 H.sub.5, H, COOCH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3 being free from amino groups, nitro group, chloride and fluoride. The above novel titanocene derivatives represent a compromise between the two main properties required for an antitumor agent: electrophilicity and stability.


DETAILE

REFERENCES:
patent: 5002969 (1991-03-01), Ko/ pf-Maier et al.
Kon, L. Y. et al., J. Am. Chem. Soc., vol. 113, pp. 9027 (1991).
Murthy M. S. et al., Proc. Am. Assoc. Cancer Res., vol. 27, pp. 279 (1986).
Andra, K., J. Organomet. Chem., vol. 11, No. 3, pp. 567-570 (1968).

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